Flavivirus is a genus of viruses that includes dengue virus (DENV), West Nile virus (WNV), tick-borne encephalitis virus, and yellow fever virus (YFV), among others. Flaviviruses share several common aspects: common size (40-65 nm), symmetry (enveloped, icosahedral nucleocapsid), nucleic acid (positive-sense, single-stranded RNA of approximately 10,000-11,000 bases), and appearance in the electron microscope. Most of these viruses are transmitted by the bite from an infected arthropod and hence classified as arboviruses.
DENV is transmitted via the bite of an infected mosquito generally of the Aedes spp. during feeding and probing. DENV is the leading arbovirus in tropical areas and causes serious human disease and mortality worldwide including substantial pediatric morbidity and mortality. Infection with DENV in humans can result in dengue fever, dengue shock symptom and/or dengue hemorrhagic fever; the latter two can lead to severe disease and death.
Traditionally, dengue outbreaks have been controlled by limiting mosquito density through the use of insecticides and elimination of stagnant water. The increase in number of cases despite such vector control indicates that these strategies are not suitably effective, and that new tools need be developed to alleviate disease burden in endemic areas.
Several experimental vaccines have been developed in an attempt to limit host susceptibility to DENV but results have been disappointing thus far. One of the obstacles in dengue vaccine development is the potential risk of severe disease mediated by the presence of sub-neutralizing antibodies against virus particles. These antibodies can predispose an individual to severe disease through a phenomenon called antibody-dependent enhancement, where the virus can infect cells via FcR in mononuclear cells. Traditional vaccine approaches have included live attenuated viruses, recombinant subunits, virus-like particles and plasmid or viral vectors. There are live attenuated and chimeric DENV vaccines that have gone into clinical trials but none have proven to provide complete and lasting protection against all four DENV serotypes. There is currently no approved specific treatment, antiviral therapy, or vaccine for dengue fever, and an estimated 2 billion people globally are at risk for being infected with DENV.
A recently developed vaccine type that can complement traditional vaccines is designed to induce in the vertebrate host (infected or non-infected) an immune response that can block virus infection of the transmission vector (e.g., the mosquito). This approach can interrupt virus transmission by inducing antibody responses against non-viral antigens. These vaccine types are called transmission-blocking vaccines (TBV) as they aim to interfere with pathogen acquisition in and infection of the vector, thereby blocking downstream transmission to human hosts. TBVs have been designed to inhibit malaria infection based on the mammalian immune response to pathogen proteins. Another category of TBVs in development is based on arthropod molecules able to reduce pathogen infection in vector tissues. For arboviruses, vector molecules (e.g. ligands/receptors) that interact with the viral pathogen in the infection process have the potential to be highly suitable candidates for the transmission blocking approach.
What are needed in the art are preventative and therapeutic measures such as TBVs that can be utilized in controlling flavivirus infection such as DENV. Moreover, single vaccines capable of controlling multiple diseases through multiple targets (e.g., virus, parasite, vector) would be of great benefit.